Research Progress of Fibroblast Growth Factor Receptor Signaling Pathway in Breast Cancer / 中国医学科学院学报

Breast cancer,one of the common malignant tumors in women,has shown rising incidence in recent years,posing a serious threat to women's health.The advancement of molecular biology facilitates the revealing of the relationships between signaling pathways and breast cancer.Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in the proliferation,survival,differentiation,migration,and apoptosis of breast cancer cells.Strategies targeting the FGFR signaling pathway thus exhibit a promising prospect in breast cancer treatment.

Precision Medicine, Artificial Intelligence, and Genomic Markers in Urology. Do we need to Tailor our Clinical Practice? / Medicina de precisión, inteligencia artificial y marcadores genómicos en urología. ¿Debemos cambiar nuestra práctica clínica?

Precision medicine plays a key role in urological oncology practice nowadays, with the breakthrough of the poly (ADP-ribose) polymerase inhibitors (PARPi), which play a critical role in different DNA damage repair (DDR) pathways, the immune checkpoint inhibitors, the genomic expression profiles and current genome manipulation-directed targeted therapy. Information and technology (IT) are set to change the way we assess and treat patients and should be reviewed and discussed. The aim of the present article is to demonstrate a detailed revision on precision medicine, including novel therapeutic targets, genomic markers, genomic stratification of urological patients, and the top-notch technological breakthroughs that could change our clinical practice We performed a review of the literature in four different databases (PubMed, Embase, Lilacs, and Scielo) on any information concerning prostate, bladder, kidney and urothelial cancer novel treatments with PARPi, immune checkpoint inhibitors (ICIs), targeted therapy with fibroblast growth factor receptor inhibitors (FGFRi), and theranostics with prostate-specific membrane antigen (PSMA) targeted monoclonal antibodies. Artificial intelligence, machine learning, and deep learning algorithm in urological practice were also part of the search. We included all articles written in English, published within the past 7 years, that discussed outstanding therapies and genomics in urological cancer and artificial intelligence applied to urology. Meanwhile, we excluded articles with lack of a clear methodology and written in any other language than English. One-hundred and twenty-six articles of interest were found; of these, 65 articles that presented novel treatments of urological neoplasms, discussed precision medicine, genomic expression profiles and biomarkers in urology, and latest deep learning and machine learning algorithms as well as the use of artificial intelligence in urological practice were selected. A critical review of the literature is presented in the present article. Urology is a constantly changing specialty with a wide range of therapeutic breakthroughs, a huge understanding of the genomic expression profiles for each urological cancer and a tendency to use cutting-edge technology to treat our patients. All of these major developments must be analyzed objectively, taking into account costs to the health systems, risks and benefits to the patients, and the legal background that comes with them. A critical analysis of these new technologies and pharmacological breakthroughs should be made before considering changing our clinical practice. Nowadays, research needs to be strengthened to help us improve results in assessing and treating our patients

La medicina de precisión juega un rol fundamental en la práctica clínica de la urologia oncológica en la actualidad, con el desarrollo de los inhibidores de la poli (ADP-ribosa) polimerasa (PARPi), que juegan un papel fundamental en las distintas vías del reparo del ADN dañado (RAD), los inhibidores del punto de chequeo inmune (ICI), los perfiles de expresión genómicos, y la terapia blanco-dirigida a la manipulación genómica. El desarrollo tecnológico y la informática están cambiando la forma como evaluamos y tratamos a los pacientes, y se debe discutir y revisar a detalle. El objetivo de este artículo es hacer una revisión detallada acerca de la medicina de precisión, genómica, y los avances tecnológicos en nuestro campo. Realizamos una revisión de la literatura en cuatro bases de datos diferentes (PubMed, Embase, Lilacs, y Scielo), buscando cualquier información relacionada con cáncer de próstata, vejiga, riñón y carcinoma urotelial, tratamientos novedosos con PARPi, ICI, terapia-blanco con inhibidores del receptor del factor de crecimiento de los fibroblastos (FGFRi) y teragnósticos con anticuerpos monoclonales dirigidos al antígeno de membrana específico de la próstata (AMEP). Inteligencia artificial, aprendizaje de máquinas y algoritmos de aprendizaje profundo en la práctica urológica también fueron revisados. Incluimos artículos escritos en inglés, publicados dentro de los últimos 7 años, que abordaran terapias novedosas y genómica en cáncer urológico e inteligencia artificial aplicada a la urología. Excluimos artículos con falta de una metodología adecuada y escritos en cualquier idioma diferente al inglés. En total, 126 artículos de interés fueron encontrados, y, de estos seleccionamos 65 artículos que reportaban tratamientos novedosos para neoplasias urológicas, discutían medicina de precisión y perfiles de expresión genómica y bio-marcadores en urología, algoritmos de aprendizaje profundo, aprendizaje de máquina, y el uso de inteligencia artificial en la práctica urológica. Se hizo una revisión crítica de la literatura que se presenta en este artículo. La urología es una especialidad constantemente en cambio, con un gran rango de avances terapéuticos, un gran conocimiento de los perfiles de expresión genómica para cada cáncer urológico, y una tendencia a utilizar tecnología de punta para estudiar y tratar a nuestros pacientes. Todos estos desarrollos se deben analizar objetivamente, y hay que tener en cuenta los costos al sistema de salud, los riesgos y beneficios para los pacientes, y el contexto legal que implica cada uno. Hasta la fecha, estos avances tecnológicos y farmacológicos se deben analizar con cautela antes de vernos en la posición de cambiar nuestra práctica clínica. Se debe fortalecer la investigación médica para mejorar los resultados en el tratamiento y abordaje de nuestros pacientes.

Skeletal mineralization: mechanisms and diseases

Skeletal mineralization is initiated in matrix vesicles (MVs), the small extracellular vesicles derived from osteoblasts and chondrocytes. Calcium and inorganic phosphate (Pi) taken up by MVs form hydroxyapatite crystals, which propagate on collagen fibrils to mineralize the extracellular matrix. Insufficient calcium or phosphate impairs skeletal mineralization. Because active vitamin D is necessary for intestinal calcium absorption, vitamin D deficiency is a significant cause of rickets/osteomalacia. Chronic hypophosphatemia also results in rickets/osteomalacia. Excessive action of fibroblast growth factor 23 (FGF23), a key regulator of Pi metabolism, leads to renal Pi wasting and impairs vitamin D activation. X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary FGF23-related hypophosphatemia, and enhanced FGF receptor (FGFR) signaling in osteocytes may be involved in the pathogenesis of this disease. Increased extracellular Pi triggers signal transduction via FGFR to regulate gene expression, implying a close relationship between Pi metabolism and FGFR. An anti-FGF23 antibody, burosumab, has recently been developed as a new treatment for XLH. In addition to various forms of rickets/osteomalacia, hypophosphatasia (HPP) is characterized by impaired skeletal mineralization. HPP is caused by inactivating mutations in tissue-nonspecific alkaline phosphatase, an enzyme rich in MVs. The recent development of enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has improved the prognosis, motor function, and quality of life in patients with HPP. This links impaired skeletal mineralization with various conditions, and unraveling its pathogenesis will lead to more precise diagnoses and effective treatments.

Progress on the Study of Targeting FGFR in Squamous Non-small Cell Lung Cancer / 中国肺癌杂志

Squamous cell lung cancer (SqCLC) is a unique clinical and histologic category of non-small cell lung cancer (NSCLC). Most of patients with SqCLC tend to be older, typically at advanced stage, associated with smoking and have more complications. With progress of targeted therapy of lung cancer, we identified several potential actionable genetic abnormalities such as FGFR. Several FGFR inhibitors have been approved for clinical use in different cancers. And some of these agents are currently under investigation in clinical trials for SqCLC. This article summarizes the current knowledge about FGFR aberrations, the relative inhibitors in development and clinical data in SqCLC.

Effect of Ronghuang Granule on serum FGF23, FGFRs and Klotho in non-dialysis patients with CKD-MBD and kidney deficiency and damp-heat syndrome / 南方医科大学学报

OBJECTIVE@#To observe the effect of Ronghuang granule on serum fibroblast growth factor 23 (FGF23), fibroblast growth factor receptor (FGFRs) and Klotho protein levels in non-dialysis patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) and kidney deficiency and damp heat syndrome.@*METHODS@#Seventy non-dialysis CKD-MBD patients with kidney deficiency and dampness-heat syndrome were randomized into control group (=35) and treatment group (=35). All the patients were given routine treatment combined with traditional Chinese medicine retention enema, and the patients in the treatment group received additional Ronghuang granule treatment (3 times a day). After the 12-week treatments, the patients were examined for changes of TCM syndromes. Serum levels of Ca, P, parathyroid hormone (iPTH), FGF23, FGFRs and Klotho proteins were detected before and after treatment. These parameters were also examined in 20 healthy volunteers.@*RESULTS@#Sixty-five patients completed the study, including 33 in the control group and 32 in the treatment group. The patients in the treatment group showed significantly better treatment responses than those in the control group ( < 0.05 or 0.01). At 4, 8, and 12 weeks of treatment, the patients in the treatment group had significantly lowered scores of TCM syndromes compared with the score before treatment ( < 0.05 or 0.01), while in the control group, significant reduction of the scores occurred only at 12 weeks ( < 0.05); at each of the time points, the treatment group had significantly greater reductions in the score than the control group ( < 0.01). Significant improvements in serum Ca, P and iPTH levels were observed at 4, 8, and 12 weeks in the treatment group ( < 0.05) but only at 12 weeks in the control group ( < 0.05). The patients in the control and treatment groups all showed elevated serum levels of FGF23, FGFRs and Klotho protein compared with the normal subjects ( < 0.01); FGF23, FGFRs and Klotho levels were significantly reduced in the treatment group ( < 0.05) but remained unchanged in the control group (>0.05), showing significant differences between the two groups.@*CONCLUSIONS@#Ronghuang granule improves the clinical symptoms of non-dialysis CKD-MBD patients with kidney deficiency and dampness heat syndrome by reducing serum levels of FGF23, FGFRs and Klotho, improving calcium and phosphorus metabolism disorder, and inhibiting secondary hyperparathyroidism.

Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05) / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Fibroblast growth factor (FGF) signals are important in carcinogenesis and progression of prostate cancer. Dovitinib is an oral, pan-class inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor (FGFR). We evaluated the efficacy and toxicity of dovitinib in men with metastatic castration resistant prostate cancer (mCRPC). MATERIALS AND METHODS: This study was a single-arm, phase II, open-label, multicenter trial of dovitinib 500 mg/day (5-days-on/2-days-off schedule). The primary endpoint was 16-week progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and prostate-specific antigen (PSA) response rate. Biomarker analyses for VEGFR2, FGF23, and FGFR2 using multiplex enzyme-linked immunosorbent assay was performed. RESULTS: Forty-four men were accrued from 11 hospitals. Eighty percent were post-docetaxel. Median PSA was 100 ng/dL, median age was 69, 82% had bone metastases, and 23% had liver metastases. Median cycles of dovitinib was 2 (range, 0 to 33). Median PFS was 3.67 months (95% confidence interval [CI], 1.36 to 5.98) and median OS was 13.70 months (95% CI, 0 to 27.41). Chemotherapy-naïve patients had longer PFS (17.90 months; 95% CI, 9.23 to 28.57) compared with docetaxel-treated patients (2.07 months; 95% CI, 1.73 to 2.41; p=0.001) and the patients with high serum VEGFR2 level over median level (7,800 pg/mL) showed longer PFS compared with others (6.03 months [95% CI, 4.26 to 7.80] vs. 1.97 months [95% CI, 1.79 to 2.15], p=0.023). Grade 3 related adverse events were seen in 40.9% of patients. Grade 1-2 nausea, diarrhea, fatigue, anorexia, and all grade thrombocytopenia are common. CONCLUSION: Dovitinib showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve benefitted from dovitinib.

VEGF and Ki-67 Overexpression in Predicting Poor Overall Survival in Adenoid Cystic Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). MATERIALS AND METHODS: A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS). RESULTS: In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. CONCLUSION: High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.

Clinical and gene involved of one case of 8p11 myeloproliferative syndrome with ins(13;8)(q12;p11p23) / 中华血液学杂志

<p><b>OBJECTIVE</b>To improve the understanding of patients with 8p11 myeloproliferative syndrome (EMS) harboring ins(13;8)(q12;p11p23)/ZNF198 -FGFR1.</p><p><b>METHODS</b>We reported here a 8p11 EMS case and provided more details on the clinical and molecular features of ins(13;8)(q12;p11p23)/ZNF198-FGFR1，full length ZNF198-FGFR1 was cloned by overlap extension PCR method，and the literatures on this topic were reviewed.</p><p><b>RESULTS</b>Clinically, the case with ins(13;8)(q12;p11p23)/ZNF198-FGFR1 had distinct hematological and clinical characteristics: hyperleukocytosis, myeloid hyperplasia，widespread adenopathy and lymphoma; Fluorescence in situ hybridization (FISH) disclosed the positive FGFR1 gene rearrangement; Further molecular studies confirmed a mRNA in-frame fusion between exon 17 of the ZNF198 gene and exon 9 of FGFR1 gene ，the full length ZNF198-FGFR1 was composed of a NH2 terminus of ZNF198 including the ZNF and proline-rich domains, whereas the COOH terminus of FGFR1 included 2 tyrosine kinase domains.</p><p><b>CONCLUSION</b>EMS with ins(13;8)(q12;p11p23)/ZNF198 -FGFR1 was a very rare， distinct myeloproliferative neoplasm, the fusion gene and chimeric protein with constitutive activation of the FGFR1 tyrosine kinase.</p>

Análise molecular dos genes NEUROD4, FGFR1 e PROKR2 em pacientes com hipopituitarismo congênito / Comparison between Auditory Steady-State Responses and behavioral audiometry in pediatric cochlear implant candidates

INTRODUÇÃO: As Respostas Auditivas de Estado Estável permitem avaliação frequência específica em intensidades de até 120 dB NA e a detecção de audição residual em pacientes com perda auditiva severo-profunda. O objetivo deste estudo é comparar os limiares à RAEE e os resultados da avaliação comportamental em crianças com suspeita de surdez severo-profunda. MÉTODO: Estudo transversal para comparar respostas à RAEE e por audiometria com reforço visual (VRA) em 63 crianças candidatas ao implante coclear (126 orelhas) com idade entre 6 e 72 meses. Foram incluídas crianças com otomicroscopia normal, ausência de respostas ao PEATE clique a 90 dB NA e às emissões otoacústicas. Foram excluídas crianças com malformações de orelha interna, doenças do espectro da neuropatia auditiva, ou que não completaram a avaliação comportamental ou não atingiram ruído eletroencefalográfico < 30 nV durante a RAEE. Foram utilizados estímulos com tons contínuos sinusoidais (100% AM e 20% FM) nas frequências de 500, 1000, 2000 e 4000 Hz em intensidade máxima de 110 dB NA. Os limiares à VRA foram obtidos por tom warble nas frequências de 500, 1000, 2000 e 4000 Hz em cada orelha através de fones de inserção (ER-5A) ou tipo casco (TDH-39). A intensidade máxima de estimulação foi de 120 dB NA em cada frequência. RESULTADOS: Limiares comportamentais foram obtidos em 36,7% (185/504) de todas as frequências em todas as crianças, 9% em intensidade maior que 110 dB NA. Entre as 504 medidas da RAEE em 63 indivíduos, 53 limiares foram obtidos (10,5%). Ao todo, 89,5% das frequências testadas não apresentaram nenhuma resposta em 110 dB NA. A distribuição dos limiares à RAEE foi semelhante à da avaliação comportamental. A maioria das respostas foram em 500 Hz, diminuindo nas frequências agudas. A diferença média entre os limiares à VRA e à RAEE variou entre 0,09 e 8,94 dB. Foram realizadas 27 comparações entre RAEE e VRA: 12 em 500 Hz, 9 em 1000 Hz, 5 em 2000 Hz e 1 em 4000 Hz. Respostas...

Introduction and Objective: ASSR allows frequency-specific evaluation in intensities up to 120 dB HL and detection of residual hearing in patients with severe-toprofound hearing loss. The aim of this study was to compare ASSR thresholds and behavioral test results in children with suspected severe-to-profound hearing loss. Methods: A cross sectional study was carried out to compare ASSR and Visual Reinforcement Audiometry (VRA) responses in 63 pediatric cochlear implant candidates (126 ears) aged between 6 to 72 months. We included children with normal otomicroscopy findings, absent responses to click-ABR at 90 dB HL and otoaccoustic emissions. We excluded children with inner ear malformations, auditory neuropathy spectrum disorder or who did not complete VRA or achieve EEG noise < 30 nV during the ASSR test. Air-conduction ASSR stimuli were continuous sinusoidal tones (100% AM and 20% FM) presented at 0.5, 1, 2 and 4 kHz starting at the maximum presentation level of 110 dB HL. VRA thresholds were acquired with warble tones presented at 0.5, 1, 2 and 4 KHz in each ear through ER-tone 5A or TDH-39 phones. Maximum presentation level was 120 dB HL for each frequency. Results: Behavioral thresholds were obtained in 36.7% (185/504) of all frequencies in all subjects, 9% were in intensities > 110 dB HL. Among 504 ASSR measurements from 63 subjects, 53 thresholds were obtained (10.5%). Overall 89.5% of the tested frequencies did not show any response at 110 dB HL. The distribution of ASSR responses was similar to the behavioral test results. Most responses were at 500 Hz, decreasing among the higher frequencies. Mean differences between behavioral and ASSR thresholds varied from 0.09 to 8.94 dB. Overall, 27 comparisons of behavioral and ASSR thresholds were obtained: 12 at 0.5 KHz, 9 at 1 KHz, 5 at 2 KHz and 1 at 4 KHz. Absent responses were observed in both tests in 38.1% at 0.5 KHz, 52.4% at 1 KHz, 74.6% at 2 KHz and 81.0% at 4 KHz. The specificity was > 90% at 1,...

Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma

BACKGROUND/AIMS: Fibroblast growth factor signaling is involved in hepatocarcinogenesis. The aim of this study was to determine the fibroblast growth factor receptor (FGFR) isotype expression in hepatocellular carcinoma (HCC) and neighboring nonneoplastic liver tissue, and elucidate its prognostic implications. METHODS: Immunohistochemical staining of FGFR1, -2, -3, and -4 was performed in the HCCs and paired neighboring nonneoplastic liver tissue of 870 HCC patients who underwent hepatic resection. Of these, clinical data for 153 patients who underwent curative resection as a primary therapy were reviewed, and the relationship between FGFR isotype expression and overall survival was evaluated (development set). This association was also validated in 73 independent samples (validation set) by Western blot analysis. RESULTS: FGFR1, -2, -3, and -4 were expressed in 5.3%, 11.1%, 3.8%, and 52.7% of HCCs, respectively. Among the development set of 153 patients, FGFR2 positivity in HCC was associated with a significantly shorter overall survival (5-year survival rate, 35.3% vs. 61.8%; P=0.02). FGFR2 expression in HCC was an independent predictor of a poor postsurgical prognosis (hazard ratio, 2.10; P=0.02) in the development set. However, the corresponding findings were not statistically significant in the validation set. CONCLUSIONS: FGFR2 expression in HCC could be a prognostic indicator of postsurgical survival.

Mutational identification of fibroblast growth factor receptor 1 and fibroblast growth factor receptor 2 genes in craniosynostosis in Indian population.

OBJECTIVE: The Objective of this study was to identify the association of mutation of fibroblast growth factor receptor 1 (FGFR1), FGFR2 genes with syndromic as well as non‑syndromic craniosynostosis in Indian population. MATERIALS AND METHODS: Retrospective analysis of our records from January 2008 to December 2012 was done. A total of 41 cases satisfying the inclusion criteria and 51 controls were taken for the study. A total volume of 3 ml blood from the patient as well as parents was taken. Deoxyribonucleic acid extracted using phenol chloroform extraction method followed by polymerase chain reaction‑restriction fragment length polymorphism method. RESULTS: There were 33 (80.4%) non‑syndromic cases of craniosynostosis while 8 (19.5%) were syndromic. Out of these 8 syndromic cases, 4 were Apert syndrome, 3 were Crouzon syndrome and 1 Pfeiffer syndrome. Phenotypically the most common non‑syndromic craniosynostosis was scaphocephaly (19, 57.7%) followed by plagiocephaly in (14, 42.3%). FGFR1 mutation (Pro252Arg) was seen in 1 (2.4%) case of non‑syndromic craniosynostosis while no association was noted either with FGFR1 or with FGFR2 mutation in syndromic cases. None of the control group showed any mutation. CONCLUSION: Our study proposed that FGFR1, FGFR2 mutation, which confers predisposition to craniosynostosis does not exist in Indian population when compared to the western world.

Pulmonary expression levels of fibroblast growth factor receptors and lung fibrosis in mice at different ages / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the correlation of pulmonary expressions of fibroblast growth factor receptors (FGFR1-4) with lung fibrosis and aging.</p><p><b>METHODS</b>Real-time fluorescence quantitative PCR was used to detect the expression levels of FGFR1-4 in the lung tissues, and lung fibrosis was observed by HE and Masson staining in mice at different ages.</p><p><b>RESULTS</b>The 4 subtypes of FGFR showed different expression levels in the lung tissues of mice, and FGFR2 had the highest expressions. The expression levels of all the 4 FGFR subtypes in 8-month-old mice were significantly lower than those in 5-week-old mice. The 8-month-old mice tended to present with histological changes of lung fibrosis.</p><p><b>CONCLUSION</b>FGFR expressions is down-regulated with aging in mice. Among the FGFR subtypes, FGFR2 is expressed at the highest level. The occurrence of lung fibrosis with aging is probably associated with down-regulated FGFR expression. FGF/FGFR signaling may participate in the aging process and regulation of lung fibrosis.</p>

Apert and Pfeiffer Syndromes: A Report of Two Cases

Craniosysostosis syndrome is caused by premature fusion of bones of skull and face during fetal development. It is related to Fibroblast growth factor receptor gene and most common craniosynostosis syndromes are Apert, Pfeiffer and Crouzon. Apert syndrome is one of the severe type of craniosynostosis syndromes which shows mutations in the Fibroblast growth factor receptor 2 (FGFR2) gene. Pfeiffer syndrome is also related with FGFR 1 or 2 gene mutation. We experienced two patients with craniosynostosis syndromes, Apert syndrome and Pfeiffer syndrome. The first baby was a in-born female baby presented with syndactly of the hands and feet and facial dysmorphism including shallow orbit with deep crease above eye brow. Apert syndrome was confirmed by the presence of a mutation in FGFR2. The second patient visited our developmental delay clinic due to developmental delay at seven month old age. He showed facial dysmorphism including cloverleaf-shaped skull, micrognathia, low set ears, low nasal bridge and high-arched palate, but there were no syndactly or limb anomalies. He was suspected of Pfeiffer syndrome, however his FGFR2 gene study was normal. These patients need multidisciplinary team management and regular follow up for visual, auditory, and cognitive development functions Pediatricians have important role on recognizing the patients with facial dysmorphism, planning to evaluate accompanying anomalies and making appropriate decisions about the timing of surgical management to minimize growth and cognitive impairments.

Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women / 한국유방암학회지

PURPOSE: Genetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women. METHODS: Two hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: A statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk. CONCLUSION: Our findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.

Association Study of Fibroblast Growth Factor 2 and Fibroblast Growth Factor Receptors Gene Polymorphism in Korean Ossification of the Posterior Longitudinal Ligament Patients

OBJECTIVE: The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of fibroblast growth factor (FGF) 2 gene and fibroblast growth factor receptor (FGFR) genes are associated with ossification of the posterior longitudinal ligament (OPLL). METHODS: A total of 157 patients with OPLL and 222 controls were recruited for a case control association study investigating the relationship between SNPs of FGF2, FGFR1, FGFR2 and OPLL. To identify the association among polymorphisms of FGF2 gene, FGFR1, FGFR2 genes and OPLL, the authors genotyped 9 SNPs of the genes (FGF2 : rs1476217, rs308395, rs308397, and rs3747676; FGFR1 : rs13317 and rs2467531; FGFR2 : rs755793, rs1047100, and rs3135831) using direct sequencing method. SNPs data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs. RESULTS: Of the SNPs, a SNP (rs13317) in FGFR1 was significantly associated with the susceptibility of OPLL in the codominant (odds ratio=1.35, 95% confidence interval=1.01-1.81, p=0.048) and recessive model (odds ratio=2.00, 95% confidence interval=1.11-3.59, p=0.020). The analysis adjusted for associated condition showed that the SNP of rs1476217 (p=0.03), rs3747676 (p=0.01) polymorphisms in the FGF2 were associated with diffuse idiopathic skeletal hyperostosis (DISH) and rs1476217 (p=0.01) in the FGF2 was associated with ossification of the ligament flavum (OLF). CONCLUSION: The results of the present study revealed that an FGFR1 SNP was significantly associated with OPLL and that a SNP in FGF2 was associated with conditions that were comorbid with OPLL (DISH and OLF).

Establishment of a novel cell model targeted on FGF-21 receptor for screening anti-diabetic drug candidates / 药学学报

The aim of this project is to establish a fibroblast growth factor-21 (FGF-21) signaling pathway targeted cell model, for screening a class of FGF-21 receptor agonists as anti-diabetic candidates. FGF-21 requires beta klotho transmembrane proteins as co-receptor for the activation of tyrosine kinase FGF receptor (FGFR) signaling, thereby activating a series of intracellular signaling pathways and regulating gene transcription for glucose metabolism. Firstly a recombinant plasmid expressing co-receptor beta klotho and EGFP reporter genes was constructed. After introducing the recombinant plasmid into package cells, the cell culture supernatant was used to infect 3T3-L1 cells, which were then screened for stably expressing beta klotho gene. Administration of FGF-21 increased the expression of GLUT1 and stimulated GLUT1-mediated glucose uptake. This novel cell model can be conveniently used in high-throughput drug screening of FGF-21 or FGF-21 analogues.

Novel targeted agents for the treatment of bladder cancer: translating laboratory advances into clinical application: [review]

Bladder cancer is a common and frequently lethal cancer. Natural history studies indicate two distinct clinical and molecular entities corresponding to invasive and non-muscle invasive disease. The high frequency of recurrence of noninvasive bladder cancer and poor survival rate of invasive bladder cancer emphasizes the need for novel therapeutic approaches. These mechanisms of tumor development and promotion in bladder cancer are strongly associated with several growth factor pathways including the fibroblast, epidermal, and the vascular endothelial growth factor pathways. In this review, efforts to translate the growing body of basic science research of novel treatments into clinical applications will be explored.

Eosinofilia reacional, leucemia eosinofílica crônica e síndrome hipereosinofílica idiopática / Reactive eosinophilia, chronic eosinophilic leukemia and idiopathic hypereosinophilic syndrome

A eosinofilia é freqüente na prática clínica, principalmente quando os valores estão entre 500 e 1000 eosinófilos/uL e indica a presença de doença parasitária, alérgica ou reação a medicamentos. Afora essas situações, a eosinofilia pode ser devida a doenças do tecido conjuntivo, infecções e, mais raramente, a doença hematológica maligna ou a tumores sólidos. Os critérios estabelecidos na década de 70 para a definição para a definição da síndrome hipereosinofílica idiopática se tornaram insuficientes para caracterizar todas as entidades albergadas sob o termo eosinofilia e, hoje, melhor compreendidas graças aos avanços na biologia celular e molecular, que proporcionaram a caracterização de doenças distintas e que envolvem células das linhagens mieloide e linfoide. Nesse contexto, as eosinofilias sanguíneas são categorizadas como reacionais, clonais e idiopáticas (SHE). O advento de terapia antitirosinoquinase (a exemplo do mesilato de imatinibe), eficaz para os casos com o rearranjo gênico FIP1L1/PDGFR, também abriu novas perspectivas para o controle ideal da leucemia eosinofílica crônica. Daí a importância do diagnóstico preciso e rápido para a indicação terapêutica ideal, antes que se instalem as complicações orgânicas, em especial cardíacas, que são irreversíveis. O presente manuscrito objetiva rever as situações de eosinofilia sanguínea e oferecer uma atualização da investigação diagnóstica e terapêutica.

Mild eosinophilia with values of less than 1000 eosinophils/µL is commonly seen in the clinical practice and can be secondary to parasitic, inflammatory or allergic diseases or to drug reactions. Additionally, eosinophilia may be due to connective tissue disorders, infections and occasionally to hematopoietic malignancies or solid tumors. The criteria established in the 1970s, for the definition of idiopathic hypereosinophilic syndrome is today unsatisfactory to characterize all conditions described as eosinophilia. Now these conditions are better understood due to the evolution of cellular and molecular biology. This knowledge has helped to characterize distinct disorders involving myeloid and lymphoid lineages. Hence, eosinophilia is categorized as reactive, clonal or idiopathic. With the introduction of anti-tyrosine kinase (imatinib mesylate) therapy, which is effective for the FIP1L1/PDGFRa rearrangement, there is a possibility to control or cure chronic eosinophilic leukemia. For this reason, precise and fast diagnosis is necessary for ideal therapeutic decisions before organic lesions that are irreversible, such as heart injury, become established. The aim of this manuscript is to review eosinophilia and offer an update on diagnostic and therapeutic investigations.

Papel da via lkaros-FGFR4 na evolução pós-cirúrgica dos pacientes com Doença de Cushing / Ikaros-FGFR4 pathway role in the postoperative outcome of Cushing's Disease

Os mecanismos envolvidos na patogênese molecular dos tumores hipofisários corticotróficos são complexos, heterogêneos e permanecem na maioria dos casos desconhecidos. Alterações da expressão de componentes da via Ikaros (Ik), tais como do receptor 4 dos fatores de crescimento de fibroblastos (FGFR4) têm sido detectadas em tumores hipofisários, inclusive nos corticotropinomas. O desbalanço entre as isoformas longas e curtas do Ikaros resulta em um início de transcrição alternativa do FGFR4, codificando uma isoforma truncada do gene (pdt- FGFR4) que foi associada a tumores hipofisários maiores e mais invasivos. A isoforma curta Ik6 promove a expressão do fator anti-apoptótico Bcl-XL in vitro, um efeito independente da interação com as isoformas longas. Além disso, um polimorfismo do FGFR4, com substituição da glicina por arginina no códon 388 (G388R), tem sido associado à evolução desfavorável em vários tipos tumorais humanos. Objetivos: Analisar a expressão do Bcl-XL, das isoformas do Ikaros (Ik1+Ik2/Ik total) e do FGFR4 em corticotropinomas humanos. Avaliar a freqüência dos genótipos do códon 388 do FGFR4 nos pacientes com doença de Cushing e sua associação com a evolução pósoperatória após a primeira cirurgia transesfenoidal. Métodos: Noventa e sete pacientes com diagnóstico de doença de Cushing foram estudados. Os dados clínicos, hormonais e histopatológicos foram avaliados retrospectivamente. O estudo da expressão do Bcl-XL, do Ikaros, e do FGFR4 foi realizado por PCR em tempo real em 20 amostras de corticotropinomas, sendo dois tumores correspondentes à síndrome de Nelson. A determinação dos genótipos no códon 388 do FGFR4 foi realizada nos 97 pacientes e em 103 indivíduos controles, por PCR de fragmento do exon 9 do gene FGFR4 seguida de digestão com a enzima de restrição BstNI. A evolução pós-operatória (remissão/recidiva) da doença de Cushing foi avaliada em 76 pacientes. Foram considerados em remissão aqueles pacientes com níveis normais...

The mechanisms involved in the molecular pathogenesis of corticotroph pituitary tumors are complex, heterogeneous and in most cases remain unknown. Changes in the expression of components of Ikaros (Ik) pathway, such as receptor 4 of fibroblast growth factor (FGFR4), have been detected in pituitary tumors including corticotropinomas. Imbalance between long and short Ik isoforms results in alternative transcription initiation of FGFR4 and encodes a truncated isoform of the gene (pdt-FGFR4) which was associated with larger and more invasive pituitary tumors. The Ik6 short isoform promotes Bcl-XL expression in vitro, an effect independent of the interaction with the long isoforms. In addition, a polymorphism of FGFR4 gene, the substitution of glycine by arginine at codon 388 (G388R), has been associated with adverse outcome in several human tumor types. Objectives: To analyze the expression of Bcl-XL, Ikaros isoforms (Ik1 + Ik2/Ikaros total), and FGFR4 in human corticotropinomas. To determine the frequency of each genotype at codon 388 of FGFR4 in patients with Cushing's disease and its association with the postoperative outcome after the first transsphenoidal surgery. Methods: Ninety-seven patients with Cushing's disease were evaluated. Clinical, hormonal and histopathological findings were assessed retrospectively. The expression of Bcl-XL, Ikaros and FGFR4 were evaluated by real-time PCR in 20 samples of corticotropinomas, including two samples of Nelson's syndrome. The FGFR4 genotype was determined in the 97 patients and 103 control subjects by PCR fragment of exon 9 of the FGFR4 gene, followed by digestion with the BstNI restriction enzyme. The postoperative outcome (remission/relapse) of Cushing's disease was assessed in 76 patients. The patients with normal urinary cortisol levels during the first year after surgery, in the absence of hormone replacement therapy, and those who...

Expression of Fibroblast Growth Factor Receptor 3 in the Recurrence of Non-Muscle-Invasive Urothelial Carcinoma of the Bladder

PURPOSE: The fibroblast growth factor receptor 3 (FGFR3) gene is known to be frequently mutated in noninvasive urothelial carcinomas of the bladder. In this study, we investigated the expression of FGFR3, Ki-67, and p53 in bladder cancers and the effects of expression on tumor recurrence. MATERIALS AND METHODS: Fifty-five cases of primary bladder cancer were examined by immunohistochemistry. The relationship of these markers with various clinicopathological factors, including recurrence, was assessed. RESULTS: Positivity for cytoplasmic FGFR3 (FGFR3-c) was associated with a lower cancer grade (p=0.022) and stage (p=0.011). Recurrence was more frequent in patients with a higher stage, negative FGFR3-c, and high Ki-67 expression. According to univariate analysis, predictors of recurrence-free survival included the following: age, stage, FGFR-c, Ki-67, and p53. However, none of these was independent from the other parameters in multivariate studies. CONCLUSIONS: The immunohistochemical expression of FGFR3 is not only one of the characteristic features of lower-grade and lower-stage urothelial carcinoma but also a possible marker in predicting disease recurrence.